Genetic and epigenetic mechanisms collaborate to control SERPINA3 expression and its association with placental diseases

Abstract

SERPINA3 (Serpin peptidase inhibitor clade A member 3), also known as a1-antichymotrypsin, is a serine protease inhibitor involved in a wide range of biological processes. Recently, it has been shown to be up-regulated in human placental diseases in association with a hypomethylation of the 5' region of the gene. In the present study, we show that the promoter of SERPINA3 is transcriptionally activated by three transcription factors (TFs) (SP1, MZF1 and ZBTB7B), the level of induction being dependent on the rs1884082 single nucleotide polymorphism (SNP) located inside the promoter, the T allele being consistently induced to a higher level than the G, with or without added TFs. When the promoter was methylated, the response to ZBTB7B was allele specific (the G allele was strongly induced, while the T allele was strongly down-regulated). We propose an adaptive model to explain the interest of such a regulation for placental function and homeostasis. Overexpression of SERPINA3 in JEG-3 cells, a trophoblast cell model, decreased cell adhesion to the extracellular matrix and to neighboring cells, but protects them from apoptosis, suggesting a way by which this factor could be deleterious at high doses. In addition, we show in different human populations that the T allele appears to predispose to Intra Uterine Growth Restriction (IUGR), while a G allele at a second SNP located in the second exon (rs4634) increases the risk of preeclampsia. Our results provide mechanistic views inside the involvement of SERPINA3 in placental diseases, through its regulation by a combination of epigenetic, genetic and TF-mediated regulations.

Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes

“…The reduced expression of SERPINA3 raises a number of atrophy human diseases, including chronic obstructive pulmonary disease, Parkinson’s disease, Alzheimer’s disease, Stroke, Cystic Fibrosis and Cerebral Hemorrhage [6, 9, 10, 20, 21]. ApoA4, an endogenous protein secreted from the intestine as a novel ligand of NR4A1, increases SERPINA3; which implies that ApoA4 may be involved in regulating the above diseases, and can be utilized as a therapy target.…”

“…Its major target is the cathepsin family, a pro-inflammatory enzyme released at sites of inflammation, which contributes to the activation of inflammatory cytokines, the degradation of pathogens, and the remodeling of tissues [8]. Therefore, by inhibiting cathepsin G, SERPINA3 should limit inflammation, coagulation, extracellular matrix remodeling and apoptosis [9]. SERPINA3 has been involved in the pathology of a number of devastating human diseases including Parkinson’s disease and Alzheimer’s disease.…”

Proteomic Profiles of the Embryonic Chorioamnion and Uterine Caruncles in Buffaloes (Bubalus bubalis) with Normal and Retarded Embryonic Development1

“…Retarded caruncles showed up-regulation of serpin A3-8 (a1-antichymotrypsin), suggesting a role in placental development in the buffalo. In this regard, serpin A3-8 was upregulated in human placental diseases in association with hypomethylation of the 5 0 region of the gene [80], and its involvement in placental diseases occurs through its strict regulation by a combination of epigenetic, genetic, and transcription-factor mediated pathways [81]. The up-regulation of proteins with protease inhibitor activity in both retarded chorioamnions and retarded caruncles suggests a disequilibrium in proteolytic control that, to date, has only been described as a cause of human pre-eclampsia [82,83].…”

Differential Methylation of Genes Associated with Cell Adhesion in Preeclamptic Placentas

“…Consequently, progress has been made in identifying global methylation profiles in the PE placenta as several studies have performed methylation arrays [20]–[22]. Additionally, there are several studies to date that have investigated alterations in gene specific DNA methylation within the PE placenta including SERPINA3 [23], [24], MMP-9 [25], STOX1 [26] and Syncytin-1 [27]. However, only one study has demonstrated that methylation of a placental gene ( CYP24A1 ) can affect placental function, specifically, regulating the level of active vitamin D at the feto-maternal interface [28].…”